The goal of this research is to devise liposomal drugs that are targeted to CD44, a cell surface marker that is over-expressed on many human cancers and on cancer stem cells. To accomplish this goal we have devised a hyaluronan (HA)-lipid ligand that binds to CD44. We will create lipids with superior properties for the formation of targeted HA liposomes (HAL) and use them to encapsulate drugs in early phase clinical trials (so called 'new drugs'). The HAL drugs will be evaluated in CD44 expressing tumors. CD44 is a cell surface receptor that is part of a complex biochemical/physiological system involved in the synthesis, degradation and signaling of HA. The principle ligand for CD44 is HA itself, a high molecular weight carbohydrate polymer that consists of a two-sugar repeat. One consequence of the dysregulation of the HA system in cancer is that CD44 becomes over-expressed in: breast, prostate, colon, glioblastoma, head/neck, ovarian and pancreatic cancers. Recently, CD44 was found to be expressed at high levels on cancer stem cells, which are considered essential for rapid tumor proliferation and tumor metastases. Thus CD44 is a promising target. We will pursue the following aims: Specific aim 1: Synthesis of novel lipids, the HA-lipid ligand and use them to assemble liposomes with optimized drug delivery properties. The innovative lipids have modified head- groups where the positive charge is at the bilayer interface and negative charge is in the aqueous phase (inverse zwitterlipids). We will further characterize the sterol-modified lipids synthesized in the past period, produce single-species HA-lipids that target CD44 and can be facilely inserted into pre-existing liposomes. These new lipids will be used to create HAL with optimized release rates for 'new drugs'. Specific aim 2: Evaluation of 'new drugs' for synergy so they can be used in combination therapy as liposome therapeutics. We will identify the best 'new drugs' to use in combination with established cytotoxic drugs known to be deliverable in current liposomes. Specific aim 3: Determination of the antitumor effects of targeted liposomal drugs identified to be synergistic in aim 2 in CD44 positive murine tumors. These studies test the hypothesis that targeting established and 'new drugs' to CD44 provides superior anti-tumor effects compared to drugs delivered in non-targeted liposomes. Importantly, we will identify an optimized single species for the HA-ligand and will test the hypothesis that drugs with demonstrated synergy in culture retain synergy in murine tumor models when targeted to CD44 in separate HAL. Successful completion of our plan will address the questions: Is CD44 the right target? Are HA-liposomes the right carrier? If so, HAL drugs are ideal clinical trial candidates to treat a variety of aggressive human cancers.